Buchheit K H, Gamse R, Giger R, Hoyer D, Klein F, Klöppner E, Pfannkuche H J, Mattes H
Sandoz Pharma Limited, Basel, Switzerland.
J Med Chem. 1995 Jun 23;38(13):2331-8. doi: 10.1021/jm00013a010.
A number of substituted indole carbazimidamides were prepared and evaluated as 5-HT4 receptor agonists by using the isolated field-stimulated guinea pig ileum preparation. Their selectivity for the 5-HT4 receptor was established by examining their affinity for other 5-HT receptors using radioligand-binding techniques. Several selective and highly potent full as well as partial agonists emerged from this study. For example, 1b,d were found to be the most potent, full 5-HT4 receptor agonist described so far (EC50 = 0.5 and 0.8 nM, respectively), being 6 and 4 times more potent than serotonin itself. On the other hand, 5b and 1h appeared as partial 5-HT4 receptor agonists in the nonstimulated guinea pig ileum preparation with potencies, evaluated against serotonin action, respectively similar (5b, Ki = 12 nM) to and 300-fold higher (1h, Ki = 0.04 nM) than serotonin.
制备了多种取代吲哚碳酰亚胺酰胺，并通过使用离体场刺激豚鼠回肠标本评估其作为5-HT4受体激动剂的活性。通过放射性配体结合技术检测它们对其他5-HT受体的亲和力，确定了它们对5-HT4受体的选择性。该研究中出现了几种选择性和高效的完全激动剂以及部分激动剂。例如，发现1b、d是迄今为止描述的最有效的完全5-HT4受体激动剂（EC50分别为0.5和0.8 nM），其效力比5-羟色胺本身高6倍和4倍。另一方面，在未刺激的豚鼠回肠标本中，5b和1h表现为部分5-HT4受体激动剂，相对于5-羟色胺的作用评估，其效力分别与5-羟色胺相似（5b，Ki = 12 nM）和比5-羟色胺高300倍（1h，Ki = 0.04 nM）。
